Drugs with shorter half-life require to be provided in sustained release dosage forms to avoid multiple dosing in a day, which usually affects patient compliance. Such dosage forms should be designed in such a way that they reach the right place at right time in effective form. Polymers of natural and synthetic origins have been used extensively to modify release rate of drugs. Amongst other factors, drug loading and its solubility, the polymer swelling and dissolution behaviour in the body fluid influence the drug release rate. The pH independent polymers like hydroxypropyl methyl cellulose, polyethylene oxide, ethylcellulose, carboxymethyl cellulose and guar gum are the polymers most widely used to obtain sustained release dosage forms.
References may be made to U.S. Pat. No. 6,312,724, wherein a sustained release formulation of diclofenac sodium using hydroxyethyl cellulose prepared by direct compression method is disclosed.
References may be made to U.S. Pat. No. 5,945,125, wherein a preparation of controlled release tablet using polyethylene oxide as water swellable polymer is disclosed and showed the zero order release of incorporated drug.
References may be made to U.S. Pat. No. 5,422,123, wherein a tablet composition with zero order release behaviour has been disclosed. The tablet comprises a gelling polymer in the core and is partially covered with supporting layer of polymer which is slowly soluble in aqueous medium.
Sustained release formulations based on pH independent hydrophilic polymers deliver the drug depending on drug solubility at pH of the physiological medium. This leads to dose dumping at particular site in the gastrointestinal tract wherein the drug is highly soluble. There are many drugs which benefit from prohibiting their release in the stomach for example, the drugs which undergo degradation at acidic pH, the drugs which create gastric inflammation and the drugs which induce nausea and vomiting. These types of drugs need to be formulated in such way that the dosage form should suppress drug release in the stomach and release it slowly along the intestinal tract. This could be possible by formulating the drug using pH dependent anionic polymers as they are insoluble at acidic pH prevalent in the stomach and soluble in near neutral pH prevalent in the intestine. Currently available polymers like cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate and Eudragit L are insoluble at acidic pH. However they dissolve rapidly at near neutral and alkaline condition.
References may be made to Journal “O. S. Silva, C. R. F. Souza, W. P. Oliveira and S. C. S. Rocha, Drug Development and Industrial Pharmacy, 32, 661-667, 2006” wherein the release behaviour of Eudragit L-30D-55 coated diclofenac sodium granules is described. The drug, microcrystalline cellulose and polyvinylpyrrolidone K-30 were wet granulated and then coated with pH sensitive polymer Eudragit L-30D-55. The coated granule did not release the drug at acidic pH and released it rapidly at near neutral pH.
The rapid dissolution at near neutral pH renders these polymers unsuitable for the development of sustained release formulation even though they could maintain integrity at acidic pH. These polymers are being used as an enteric coating for the dosage forms wherein the drug release is to be avoided in the stomach.
References may be made to patent application WO 03099203 A2, wherein Gonzales Gilbert et al. disclosed an enteric coated caffeine delivery system. The drug containing core was coated with pH sensitive polymer dispersion Eudragit L100-55. The system comprised a seal coat of hydrophilic polymer like hydroxypropyl methyl cellulose between the core and an enteric coat. It has been claimed that the formulations did not release the drug in stomach and released the same rapidly in intestine. This would avoid the irritation in the stomach often caused by the caffeine if it were to be released in stomach.
Similarly, the drugs which rapidly undergo degradation at acidic pH of the stomach must be protected within the dosage forms. For example, didanosine is an acid labile drug which should be protected in the stomach before it is delivered in the intestine. References may be made to U.S. Pat. No. 6,569,457, wherein a didanosine composition coated with an enteric polymer Eudragit L-30D-55 is reported. The formulation was claimed to be intact at acidic pH condition and protect the drug from degradation and release the content rapidly at near neutral pH.
References may be made to Journal “Giovanni Filippo Palmieri, Simona Michelini, Piera Di Martino and Sante Martelli, Drug Development and Industrial Pharmacy, 26, 837-845, 2000” wherein enteric polymer for the development of sustained release formulations is described. Paracetamol tablets were prepared using various enteric polymers such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, Eudragit L and Eudragit S. The tablets were prepared by direct compression and microsphere compression methods. It was reported that the directly compressed tablets exhibited neither enteric property, nor sustained release of paracetamol. The microsphere compressed tablets comprising cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate and Eudragit S exhibited enteric property and sustained release of drug when the drug and polymer ratio was 1:8. However, Eudragit L based formulation exhibited neither enteric property nor sustained release of drug.
Currently, the sustained release of drug in the intestinal region has been achieved by using combination of pH independent and pH dependent polymers.
References may be made to U.S. Pat. No. 4,863,744 wherein system comprised drug loaded tiny reservoirs coated with pH independent polymer placed within pH sensitive anionic polymer is reported. The integrity of dosage form at pH 3.5 was facilitated by the pH sensitive anionic polymer coating. Upon dissolution of this coating at near neutral condition, the tiny reservoirs were exposed to the medium and released the drug over an extended period of time.
References may be made to patent application WO 2005/030179 A1, wherein Cho et al. developed a sustained release composition of cardiovascular drug. The formulation was designed to control the initial burst release of drug. A tablet comprising a drug and a pH independent hydrophilic polymer was coated with an enteric polymer. An additional drug layer comprising a pH independent or pH dependent polymer was provided over the enteric coat.
References may be made to U.S. Pat. No. 4,968,508, wherein Oren et al. disclosed a sustained release composition comprising a basic drug which is highly soluble at acidic pH prevalent in stomach. The formulation comprised a core tablet loaded with drug and a hydrophilic polymer which was then coated with an enteric polymer. It was claimed that the formulation suppressed the drug release in the stomach and sustained release in intestinal region.
References may be made to U.S. Pat. No. 6,893,661 A1, wherein Odidi et al. disclosed a controlled release formulation. It comprised a drug and combination of hydrophilic and hydrophobic polymer in the form of a tablet. In order to impart stealth characteristics to the tablet, so as to avoid dose dumping and food effects in the stomach, the tablet was coated with an enteric polymer.
Drugs which undergo degradation under the acidic environment of stomach need to be protected within the dosage form. Proton pump inhibitors are used to control gastric acid secretion which often leads to diseases like gastric and duodenal ulcer. References may be made to patent application EP 1043976 B1, wherein Karehill et al. disclosed an extended release dosage form of proton pump inhibitors. The drug containing granules was prepared by using a pH independent hydrophilic or hydrophobic polymer and compressed in to a tablet. The tablet was coated with an enteric polymer. An optional coat between the drug core and the enteric coat was provided.
References may be made to U.S. Pat. No. 6,274,173 B1, wherein delayed release dosage form comprising a proton pump inhibitor was disclosed for the treatment of gastric disorders is mentioned. The dosage form was prepared by granulating the drug and other ingredients to form a tablet. A release retarding layer of pH independent polymer and an enteric coating was applied on the tablet.
References may be made to US patent application 2008/0026060 A1, wherein Zerbe et al. disclosed a controlled release composition of antidepressant drug bupropion in combination with smoking cessation aid like mecamylamine. The delivery system was developed by formulating granules of stabilized bupropion and hydroxyalkyl cellulose with mecamylamine. The granule was dispersed in a sustained release polymer and then compressed into a tablet. The coating of above tablet with an enteric polymer enhanced the stability of bupropion on storage.
Non-steroidal anti-inflammatory drugs (NSAID) are known to cause gastric irritation and bleeding when they released in stomach. An ideal dosage form containing NSAID should delay the drug release until it reaches intestine. References may be made to patent application WO02/34240 A2, wherein such a delayed and sustained release composition of NSAID was disclosed for the pain management. The dosage form comprises an inert pellet such as non-peril seeds coated by a layer containing the drug followed by a rate controlling layer of water insoluble polymer and finally an enteric polymer layer.
There are some drugs which cause nausea and vomiting when released in stomach. Paroxetine is such a drug being used for the treatment of depression. Delivery systems for this kind of drug have to be designed in such a way that the drug release does not take place in the stomach and release over an extended time period takes place in the intestine. References may be made to patent application WO 2007/052877, wherein Kim et al. disclosed such a formulation which is a tablet comprising a drug and pH independent hydrophilic polymer like hydroxypropyl methyl cellulose coated with an enteric polymer. A seal coat was provided to avoid the interaction between the drug in the core and enteric polymer.
Venlafaxine is an antidepressant drug with shorter half-life and a once daily dosage form which avoids multiple dosing in a day is highly desirable. The problem associated with this drug is side effects such as nausea and emesis when the drug is released in the stomach. References may be made to patent application WO 2007/143290 A2, wherein venlafaxine composition disclosed by Vishnupad in provides an extended release of drug after a predetermined time lag. The dosage form is a compressed core comprising drug and a pH independent hydrophilic polymer coated with a combination of water insoluble polymer and an enteric polymer.
Disorders associated with post awakening period in the morning have to be treated with once daily bedtime dosage forms to enhance the patient compliance. Such dosage form should delay the drug release after ingestion and then release the content over extended period time so as to maintain the effective plasma concentration in the morning. References may be made to patent application WO 2004/091583 A1, wherein Mehta disclosed such a chrono delivery formulation for the treatment of early morning pathologies such as arthritis, angina, atrial fibrillation and hypertension. The dosage form comprised a core coated with a drug layer followed by multiple numbers of layers one over another in the sequence of seal coat of water soluble polymer, a rate controlling layer of water insoluble polymer and an enteric polymer.
References may be made to patent application WO97/48386, wherein Chen disclosed a once daily formulation of cardiovascular drug diltiazem hydrochloride. The tablet comprised a drug and pH independent hydrophilic polymer like hydroxypropyl methyl cellulose. The tablet was given an enteric coating to avoid the drug release in stomach which would result in higher plasma concentration of drug at earlier stage. It is evident from the above disclosures that the pH independent hydrophilic polymer can not suppress the drug release under the acidic condition of stomach. This leads to dose dumping and initial burst release of the drug, especially when drug is highly soluble at acidic pH of the stomach. Also some drugs should not be released within the stomach as they induce gastric inflammation or undergo degradation. Still some other drugs have to be delivered after a delay time for the treatment of chronic diseases. The currently available pH sensitive polymers do not provide sustained release of drug in intestine apart from eliminating the release under acidic environment of stomach. It is well known that dosage forms which offer pH dependent drug release are necessary for the treatment of many diseases.
Currently this has been achieved by using a combination of pH independent hydrophilic or hydrophobic polymers and a pH sensitive polymer. Therefore there is a need for pH dependent drug delivery system which does not require multiple numbers of polymers and multilayered construction. This will make processing the preparation of dosage forms easier. The present invention provides formulations which suppress the drug release at pH prevalent in the stomach and releases over an extended period of time at pH prevalent in the intestinal region.